The present invention relates to new chromene compounds.
Apart from the fact that the compounds of the present invention are new, they have particularly valuable properties, binding selectively to D3 receptors compared with D2 receptors.
The discovery of those D3 dopaminergic receptors (P. Sokoloff et al., Nature, 1990, 347, 147), their strong concentration in the limbic system and their low density in lactotrophic cells and in the nigrostriated system, makes them a choice target for obtaining antipsychotics that do not have effects on the secretion of prolactin and are less liable to cause extrapyramidal-type syndromes. It has, in fact, been established that the dopaminergic pathways extending to the limbic system and the cortex play a decisive role in the control of mood and in the aetiology and treatment of psychiatric Aid disorders such as schizophrenia, depression, anxiety, aggression and other impulsive disorders (M. J. Milian et al., Drug News and Perspectives, 1992, 5, 397-406; A. Y. Deutch et al., Schizophrenia, 1991, 4, 121-156; H. Y. Meltzen et al., Pharmacol. Rev., 1991, 43, 587-604).
The compounds of the prior art closest to those forming the subject of this Application were described for their dopaminergic or serotoninergic properties (EP 691342; J. Med. Chem., 1989, 32, 720-7).
The compounds of the present application are characterised by the presence of carboxamide or nitrile-type electron-attracting substituents which, surprisingly, allow enhancement of the D3 dopaminergic properties in terms of strength and selectivity. The selectivity makes the products of the invention especially valuable for use as medicaments acting on the dopaminergic system that do not have the undesirable effects of D2 ligands. In the light of results that have appeared in the literature, it is possible for them to be used in the treatment of impulsive disorders (for example those caused by drug abuse, B. Caine, Science, 1993, 260, 1814), aggressiveness (J. W. Tidey, Behavioral Pharm., 1992, 3, 553), Parkinson""s disease (J. Carlson, Neur. Transm., 1993, 94, 11), psychoses, memory disorders (P. Sokoloff et al., Nature, 1990, 347, 147), anxiety and depression (P. Willner, Clinical Neuropharm., 1985, 18, suppl. 1, 549-56).
The present invention relates more specifically to compounds of formula (I): 
wherein:
m is an integer such that 0xe2x89xa6mxe2x89xa63,
n is an integer such that 0xe2x89xa6nxe2x89xa63 and 2xe2x89xa6m+nxe2x89xa63,
p is an integer such that 1xe2x89xa6pxe2x89xa66,
the junction between the B and C rings is in the trans configuration,
X represents a cyano group or a group xe2x80x94COxe2x80x94NR4R5, R4 and R5 being selected from hydrogen, linear or branched (C1-C6)-alkyl, (C3-C7)-cycloalkyl and optionally substituted aryl,
A represents a "sgr" bond or a group selected from xe2x80x94NRxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NRxe2x80x94, xe2x80x94NRxe2x80x94SO2 and xe2x80x94SO2xe2x80x94NR wherein R represents a hydrogen atom or a linear or branched (C1-C6)-alkyl group,
R1 and R2 each independently represent a hydrogen atom or a linear or branched (C1-C6)-alkyl group,
R3 represents:
a hydrogen atom, or a phenyl, naphthyl or heteroaryl group each of which is optionally substituted by one or more halogen atoms, linear or branched (C1-C6)-alkyl, linear or branched (C1-C6)-alkoxy, hydroxy, cyano, amino, nitro, carboxy, linear or branched (C1-C6)-perhaloalkyl, sulpho, acylamino, linear or branched (C1-C6)-alkylsulphonyl or linear or branched (C1-C6)-alkylsulphonylamino groups,
an aryl or heteroaryl group substituted by a group Axe2x80x2-Cy wherein Axe2x80x2 represents a "sgr" bond, a linear or branched (C1-C6)-alkylene group (in which a carbon atom may optionally be replaced by an oxygen or sulphur atom), a linear or branched (C1-C6)-alkenylene group (in which a carbon atom may optionally be replaced by an oxygen or sulphur atom) or a group xe2x80x94NRxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR, xe2x80x94NRxe2x80x94SO2xe2x80x94 or SO2xe2x80x94NR (in which R represents a hydrogen atom or a linear or branched (C1-C6)-alkyl group), and Cy represents an optionally substituted aryl group or an optionally substituted heteroaryl group,
a 2-indolinon-5-yl group,
or an aryloxy or arylthio group (with the proviso that in that case A represents a "sgr" bond),
xe2x80x83provided that:
when n is 0, m is other than 2,
when n is 1, R1 and R2 represent a hydrogen atom, A represents a "sgr" bond and p is 1, R3 is other than phenyl or pyridyl,
when n is 1, R1 and R2 represent a hydrogen atom and A represents a "sgr" bond, R3 is other than a hydrogen atom,
when n is 1, R1 and R2 represent a hydrogen atom and A represents an xe2x80x94NHxe2x80x94COxe2x80x94group, R3 is other than a hydrogen atom or a phenyl, naphthyl, or heterocyclic group selected from thienyl, furyl, pyrrolyl and pyridyl, each of those groups being optionally substituted by one or more halogen atoms or trihalomethyl, alkoxy or hydroxy groups,
their isomers, enantiomers and diastereoisomers, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric, hydrobromic, sulphuric, acetic, trifluoroacetic, lactic, malonic, succinic, glutamic, fumaric, maleic, citric, oxalic, methanesulphonic, benzenesulphonic and camphoric acid etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
An aryl group is to be understood as meaning a phenyl or naphthyl group.
A heteroaryl group is to be understood as meaning a mono- or bi-cyclic aromatic group containing from 5 to 13 chain members and from one to four hetero atoms selected from nitrogen, oxygen and sulphur, for example a furyl, pyridyl or thienyl group.
The expression xe2x80x9coptionally substitutedxe2x80x9d describing aryl and heteroaryl signifies that those groups are optionally substituted by one or more halogen atoms or linear or branched (C1-C6)-alkyl, hydroxy, linear or branched (C1-C6)-alkoxy, linear or branched (C1-C6)-perhaloalkyl, cyano, nitro, sulfo, amino, linear or branched (C1-C6)-acyl, acylamino, linear or branched (C1-C6)-alkylsulfonyl or linear or branched (C1-C6)-alkylsulpholamino groups.
The term xe2x80x9cacylxe2x80x9d, alone or in the expression xe2x80x9cacylaminoxe2x80x9d, represents a linear or branched (C1-C6)-alkylcarbonyl group or a (C3-C8)-cycloalkylcarbonyl group.
Preferably, the invention relates to compounds of formula (I) wherein m and n are each 1.
Other preferred compounds of the invention are those wherein m is 3 while n is 0.
In compounds of formula (I), X preferably represents a cyano group.
In preferred compounds of the invention, A represents a "sgr" bond or an NRxe2x80x94COxe2x80x94 or NRxe2x80x94SO2 group, R preferably being a hydrogen atom.
In compounds of formula (I), R1 and R2 each more especially represents a hydrogen atom.
Preferred R3 groups of the invention are optionally substituted phenyl or optionally substituted biphenyl groups.
Another preferred group R3 is an aryl group (more especially phenyl) substituted by a group Axe2x80x2-Cy wherein Axe2x80x2 preferably represents an NRxe2x80x94CO or NRxe2x80x94SO2 group (R being more especially a hydrogen atom) and Cy preferably represents an optionally substituted aryl group.
Another preferred R3 group is the group 2-indolinon-5-yl.
The invention relates more preferably to compounds of formula (I) wherein X represents a cyano group, m and n are each 1, R1 and R2 each represent a hydrogen atom, and p is 4 when A represents an NHCO group and R3 represents an optionally substituted phenyl group or an optionally substituted biphenyl group, or p is 1 or 2 when A represents a "sgr" bond and R3 represents an optionally substituted phenyl group or an optionally substituted biphenyl group.
The invention extends also to a process for the preparation of compounds of formula (I) which is characterised in that there is used as starting material a compound of formula (II): 
wherein X, m and n are as defined for formula (I),
which is treated
with a compound of formula (III): 
xe2x80x83wherein G represents a halogen atom or a CHO group, q is an integer such that 0xe2x89xa6qxe2x89xa66, and R1, R2 and R3 are as defined for formula (I),
to yield, after reduction when G represents a CHO group, a compound of formula (I/a): 
a particular case of compounds of formula (I) wherein X, R1, R2, R3, m, n and p are as defined for formula (I),
or with a compound of formula (IV): 
xe2x80x83wherein Y represents a halogen atom, R, R1, R2, R3 and p are as defined for formula (I) and T represents a CO or SO2 group,
to yield a compound of formula (I/b): 
xe2x80x83a particular case of compounds of formula (I) wherein X, R, R1, R2, R3, m, n and p are as defined for formula (I) and T is as defined above,
or with a compound of formula (V): 
xe2x80x83wherein Y represents a halogen atom, R, R1, R2, R3 and p are as defined for formula (I) and T represents a CO or SO2 group,
to yield a compound of formula (I/c): 
xe2x80x83a particular case of compounds of formula (I) wherein X, R, R1, R2, R3, m, n and p are as defined for formula (I) and T is as defined above,
or with a compound of formula (IIIxe2x80x2): 
xe2x80x83wherein G represents a halogen atom or a CHO group, p, R1 and R2 are as defined for formula (I) and R31 represents an aryl or heteroaryl group substituted by a halogen atom or by a carboxy, nitro or sulpho group,
to yield a compound of formula (Ixe2x80x2/a): 
xe2x80x83a particular case of compounds of formula (I/a) wherein X, R1, R2, R31, m, n and p are as defined hereinbefore,
xe2x80x83which:
when R31 represents an aryl or heteroaryl group substituted by a halogen atom, is treated with an appropriate vinyl compound, tin compound or boronic acid compound in the presence of a palladium catalyst
to yield a compound of formula (I/d): 
xe2x80x83a particular case of compounds of formula (I) wherein X, R1, R2, R31, m, n and p are as defined hereinbefore, Rxe2x80x23 represents an aryl or heteroaryl group, Axe2x80x21 represents a "sgr" bond, an alkylene group (in which a carbon atom may optionally be replaced by an oxygen or sulphur atom) or an alkenylene group (in which a carbon atom may optionally be replaced by an oxygen or sulphur atom) and Cy is as defined for formula (I),
when R31 represents an aryl or heteroaryl group substituted by a nitro group, after reduction of that group to amine, is treated with a compound of formula Clxe2x80x94COxe2x80x94Cy or Clxe2x80x94SO2xe2x80x94Cy to yield a compound of formula (I/e): 
xe2x80x83a particular case of compounds of formula (I) wherein X, R1, R2, m, n, p and Cy are as defined for formula (I), Rxe2x80x23 represents an aryl or heteroaryl group and Axe2x80x22 represents an xe2x80x94NRxe2x80x94CO or xe2x80x94NRxe2x80x94SO2xe2x80x94 group (R being as defined for formula (I)),
when R31 represents an aryl or heteroaryl group substituted by a sulpho or carboxy group, is treated with a compound of formula HNRxe2x80x94Cy to yield a compound of formula (I/f): 
xe2x80x83a particular case of compounds of formula (I) wherein X, R1, R2, m, n, p and Cy are as defined for formula (I), Rxe2x80x23 represents an aryl or heteroaryl group and Axe2x80x23 represents a xe2x80x94COxe2x80x94NRxe2x80x94 or xe2x80x94SO2xe2x80x94NRxe2x80x94 group (R being as defined hereinbefore),
which compounds of formulae (I/a) to (I/f):
are purified, if necessary, according to a conventional purification technique,
are separated, where appropriate, into the enantiomers according to a conventional separation technique,
are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base,
with the proviso that when X represents a CN group it may be converted into an aminoalkyl group according to conventional techniques of organic chemistry at any stage of the synthesis.
With the aim of providing a synthesis better adapted to certain products of formula (I) it is desired to obtain, it shall be possible for certain variants of the above-described process to be used.
One such variant comprises using as starting material a compound of formula (VI): 
wherein m and n are as defined for formula (I) and R6 represents a linear or branched (C1-C6)-alkyl group,
which is treated with trifluoromethanesulphonic anhydride to yield a compound of formula (VII): 
wherein R6, m and n are as defined hereinbefore,
which compound of formula (VII) reacts with tributyltin cyanide in the presence of lithium chloride and a palladium(O) catalyst to yield a compound of formula (I/g): 
a particular case of compounds of formula (I) wherein R6, m and n are as defined hereinbefore,
which compound of formula (I/g) may, if necessary, be purified by conventional purification methods and may, where appropriate, be separated into the enantiomers by a conventional separation technique and may, if desired, be converted into an addition salt with a pharmaceutically acceptable acid or base.
The present invention relates also to the use, for the manufacture of pharmaceutical compositions for use in the treatment of disorders requiring a D3 receptor ligand, of compounds of formula (VIII): 
wherein:
represents 1 or 2,
Z represents a cyano or aminocarbonyl group,
R7 represents a linear or branched (C1-C6)-alkyl group, a benzyl group or an acylamino-(C1-C6)-alkyl group (in which the alkyl moiety is linear or branched and in which the acyl group is a benzoyl, naphthylcarbonyl, thienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl or pyridinylcarbonyl group each of which is optionally substituted by one or more halogen atoms or trihalomethyl, alkoxy or hydroxy groups),
the junction between the rings B and C is in the trans configuration, compounds (VIII) being described in the application EP 691 342.
The invention extends also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), alone or in combination with one or more inert, non-toxic excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels etc.
The useful dosage varies according to the age and weight of the patient, the nature and severity of the disorder and the administration route, which may be nasal, rectal, parenteral or oral. Generally, the unit dose ranges from 1 to 500 mg for a treatment of from 1 to 3 administrations per 24 hours.